An allergy is a pathological condition where a living body is damaged by an immune response although the response is originally a biological defense reflex. Allergic rhinitis is divided broadly into two groups. Namely, one group is perennial rhinitis caused by house dust or by mites and another group is pollinosis linked with high amounts of airborne pollen whereby many people are affected. There is a difference in symptoms between the two groups of allergies and, therefore, therapeutic methods are different. Unfortunately, once a person suffers from allergic disease, natural healing at an early stage cannot be expected and no therapeutic method to cure it completely has been established yet. Therefore, the number of patients in need of treatment is cumulatively increasing.
Bronchial asthma is a disease which is characterized by a paroxysmal dyspnea accompanied by coughs and wheezes. Although its cause is ambiguous, a theory that it is a chronic inflammatory disease of the airway has been established recently in addition to the already proposed theory of reversible obstructive impairment and hypersensitivity of the airway. Accordingly, in current therapy, steroidal preparations are used with an object of suppression of inflammation of the airway. Also, since the disease is also accompanied by an airway obstruction, anti-chemical mediators or bronchial dilators are used jointly.
Steroidal preparations used by means of inhalation, oral administration, intravenous injection, etc. are pharmaceuticals which exhibit various side effects together with a sharp clinical effect. Their main known side effects include, induction of infectious diseases, osteoporosis, arteriosclerosis, diabetes mellitus, mental disorder and moon face. It is said that serious side effects occur when administration of a steroidal preparation extends over a long period and that frequency and degree of seriousness of adrenal insufficiency is dependent upon the dose and term of the administration. Especially, withdrawal symptoms occur upon a rapid reduction of the administered dose. Additional problems include adrenal insufficiency by adrenal cortical shrinkage due to administration of high doses for a long period.
Anti-chemical mediators are pharmaceuticals which inhibit the biosynthesis and liberation of chemical mediators participating in allergy such as histamine, thromboxane and leukotriene, or pharmaceuticals which antagonize the binding of such chemical mediators to receptors. Thus, such anti-chemical mediators are not direct therapeutic agents for dilating the shrunken or contracted airway of asthma and for improving the dyspnea. They are used as pharmaceuticals for preventing the onset of asthma symptoms caused by chemical mediators.
Bronchialdilators are .beta..sub.2 stimulants and theophylline preparations are used as rapid-acting therapeutic agents for relieving the dyspnea symptom of asthma. In the case of the onset of severe asthma, therapies such as a subcutaneous injection of a .beta..sub.2 stimulant and a continuous intravenous drip of theophylline are carried out. However, in the treatment with a .beta..sub.2 stimulant, there is a problem of death by suffocation from a negative feedback due to its abuse. The theophylline preparation also has a disadvantage in that its safety region is narrow and, at high concentrations, occurrence of toxic symptoms, headache, vomiting, pulsation and extrasystole takes place. Accordingly, at present, caution for abuse is required for .beta..sub.2 stimulants, and a therapeutic drug monitoring (TDM) is carried out for theophylline preparations.
As mentioned above, the already-known therapeutic agents for bronchial asthma have both merits and demerits in terms of onset of the effect and generation of side effects. Therefore, in the practical clinical field, there has been a demand for safer, more rapidly acting pharmaceuticals.
Compounds having a pyrido[2,3-d]pyrimidine structure which have an anti-allergic action are disclosed in Japanese Laid-Open Patent Publication Sho-63/45279 and corresponding U.S. Pat. No. 4,808,587 to Go et al. Compounds having a 7-aminopyrido[2,3-d]pyrimidine structure which show a bronchial dilating action are disclosed in Japanese Laid-Open Patent Publications Hei-8/3046, Hei-8/3164 and Hei-8/3165 and their corresponding U.S. Pat. No. 5,776,942. However, in those known compounds, separation of pharmaceutical effect from side effects is not sufficient. Also, the bronchial dilating action of the known compounds is not satisfactory whereby they have not been allowed as pharmaceuticals for actual use. Additional compounds having a pyrido[2,3-d]pyrimidine structure have been reported in Japanese Laid-Open Patent Publication Hei-7/504676; Cell Signaling, 7, 527 (1995); Mol. Pharmacol., 48, 616 (1995); J. Med. Chem., 34, 624 (1991); and J. Pharmacol. Exp. Ther., 272, 3,1313 (1995)). However, these compounds are problematic in terms of their behavior in vivo such as exhibiting poor transfer into blood. None of them have been commercialized as pharmaceuticals.
None of the references disclose 7-amino-1-phenylpyrido[2,3-d]pyrimidine-2,4-dione derivatives according to the present invention. The present invention solves the above-mentioned problems and provides a therapeutic agent for bronchial asthma which is highly desirable by patients and by the medical field, i.e. an agent having high safety, rapid action, and good behavior in vivo.